EP2457562B1 - Feste Darreichungsformen mit modifizierter Freisetzung nullter Ordnung - Google Patents
Feste Darreichungsformen mit modifizierter Freisetzung nullter Ordnung Download PDFInfo
- Publication number
- EP2457562B1 EP2457562B1 EP12156178.1A EP12156178A EP2457562B1 EP 2457562 B1 EP2457562 B1 EP 2457562B1 EP 12156178 A EP12156178 A EP 12156178A EP 2457562 B1 EP2457562 B1 EP 2457562B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydrochloride
- dosage form
- coating
- modified release
- matrix core
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the present invention relates to modified release solid dosage forms suitable for administration of a wide range of water-soluble pharmaceutical agents at a zero-order release rate, and to a process of making the same. More specifically, the invention relates to modified release tablets having a matrix core containing methylphenidate hydrochloride surrounded by a modified release coating.
- Modified release dosage forms which are well known in the art, release their drug content gradually and over an extended period of time after the drug makes contact with an aqueous solution (e.g., in-vitro dissolution), or gastrointestinal fluid ( in-vivo ). These dosage forms are desirable in treating various diseases because the desired drug concentration is maintained in-vivo for longer periods of time as compared to immediate release dosage forms, allowing for less frequent dosing.
- aqueous solution e.g., in-vitro dissolution
- gastrointestinal fluid in-vivo
- the rate of drug release initially increases rapidly followed by a decreased rate of drug release.
- This type of drug release is categorized as first-order release.
- Such formulations may not produce uniform concentration levels of the drug in the bloodstream for a prolonged period of time.
- Zero-order release dosage forms are also known in the art.
- the term "zero-order release,” “zero-order dissolution” or “zero-order rate” refers to a rate of release of a drug from the solid dosage form after coming in contact with an aqueous environment, which is uniform or nearly uniform independent of the drug concentration in the dosage form during a given time period.
- Zero-order release dosage forms usually enable reduced dosing frequency compared to less sustained or more unevenly released dosage forms, thus improving patient compliance.
- Dosage forms with zero-order release generally provide maximum therapeutic value with minimal side effects.
- dose dumping The dosage form can release the drug rapidly at a high concentration, effectively "dumping" the drug into the bloodstream and potentially overdosing the patient.
- the matrix core of a modified release dosage form is often prepared by a wet granulation process.
- Wet granulation can involve milling of drugs and other ingredients, preparing a binder, mixing the binder with the milled ingredients to form a wet mass, coarse screening of the wet mass, drying of the wet mass to form granules, screening of granules, mixing the screened granules with lubricants or other excipients, extruding the mixture, and compressing to form a solid dosage form.
- Wet granulation is an expensive, time consuming process requiring many processing steps and significant capital equipment.
- U.S. Patent No. 6,673,367 reports controlled release of methylphenidate from beads coated with a sustained release coating produced by various methods of granulation.
- methylphenidate HCl is mixed with Lactose DT, Methocel, talc, magnesium stearate and optionally Eudragit L 100-55 and directly compressed into an uncoated tablet.
- Methylphenidate and methylphenidate hydrochloride are psychostimulants prescribed for the treatment of Attention Deficit Disorder (ADD), the most common psychiatric disorder in children.
- ADD Attention Deficit Disorder
- the disorder is characterized by inattentiveness and impulsiveness and may be present with hyperactivity (ADHD) as well as cognitive and learning problems.
- ADHD hyperactivity
- the mechanism of action of methylphenidate is believed to involve blocking the uptake of increased levels of extracellular dopamine and norepinephrine at nerve terminal transporters.
- the drug is a mild stimulant of the central nervous system with more prominent effects on mental activities than motor skills.
- Methylphenidate formulations with immediate release characteristics are typically administered in the morning and afternoon to ensure that a child receives an adequate dose for an 8 to 12 hour period. This requires dosing during the school day, which is preferably avoided to improve patient compliance and potential dosing errors. Patient compliance can be a problem in schools which prohibit children from taking medications during the school day or require administration only during hours when a nurse is present. Also, the rapid release of the drug into the bloodstream results in a maximum dosage for a brief period of the day with declining dosage thereafter. A substantially uniform release of the drug is more preferable so that the drug affects the child essentially consistently throughout the day.
- a sustained release form of methylphenidate (RitalinTM SR) is commercially available, but has been reported to be less effective in early morning behavior management and no more effective than immediate release dosage forms such as RitalinTM.
- Adverse side effects of methylphenidate use include hypertension, tachycardia, angina, arthralgia, dyskinesia, fever, skin rash or hives, thrombocytopenia, blurred vision or other changes in vision, convulsions, muscle cramps, Tourette's syndrome, toxic psychosis, or weight loss.
- Long-term effects of methylphenidate in children are not well established.
- the present invention is directed to a solid dosage form comprising a matrix core, a modified release coating and a water-soluble barrier coating.
- the matrix core comprises between about 10% and about 50% of a non-swellable hydrophobic material comprising at least one polymer and a water-soluble pharmaceutical agent.
- the modified release coating surrounds the matrix core, and comprises a hydrophobic polymer and a hydrophilic pore-forming agent.
- the water-soluble barrier coating is between the modified release coating and the matrix core such that the barrier coating surrounds the matrix core and the modified release coating surrounds the barrier coating.
- the solid dosage form is capable of releasing the pharmaceutical agent at a zero-order rate for a period of at least four hours after administration to a subject.
- Another aspect of the invention is directed to a method of making a solid dosage form by mixing between about 10% and about 50% of a non-swellable hydrophobic material comprising at least one polymer, from about 2 to 25 wt % of a water-soluble pharmaceutical agent, an optional filler, an optional lubricant, and an optional glidant to form a mixture, compressing the mixture to form a matrix core, coating the matrix core to form a barrier coating surrounding the matrix core, drying the barrier coating, coating the barrier-coated matrix core with a modified release coating, and drying the modified release coating to form the solid dosage form.
- the barrier coating comprises a water-soluble polymer
- the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent.
- the solid dosage form is capable of releasing the pharmaceutical agent at a zero order rate for a period of at least four hours after administration to a subject.
- the present invention provides for a modified release solid dosage form of a highly water soluble pharmaceutical ingredient, such as methylphenidate or a salt thereof, which exhibits zero-order kinetics upon dissolution.
- a dosage form eliminates the need for twice-a-day dosing, improves the likelihood of patient compliance, and establishes a substantially consistent drug dosage throughout its 6 to 10 hour period of effectiveness following administration. It also prevents or minimizes the risk of dose dumping and accidental overdose from improper dissolution of the dosage form. In the unlikely event that the coating on the dosage form ruptures, drug release from the core is still controlled by the hydrophobic material in the matrix.
- the solid dosage form can be easily prepared under ambient conditions with minimal processing steps and equipment requirements.
- the solid dosage form of the invention comprises a matrix core, a water-soluble barrier coating, and a modified release coating.
- the matrix core comprises between about 10% and about 50% of a non-swellable hydrophobic material comprising at least one polymer and a water-soluble pharmaceutically active agent, and optional excipients such as fillers, release modifiers, lubricants and glidants.
- the modified release coating is comprised of a hydrophobic polymer, a hydrophilic pore-forming agent, and an optional plasticizer.
- pore-forming agents includes materials that can be dissolved, extracted or leached from the modified release coating in the environment of use.
- the solid dosage form includes a water-soluble barrier coating between the modified release coating and the matrix core such that the barrier coating surrounds the matrix core and the modified release coating surrounds the barrier coating.
- the barrier coating also described herein as a seal coating, is comprised of a water soluble polymer and serves as a barrier between the pharmaceutically active agent in the matrix core and the modified release coating. It has been discovered that such a barrier can be effective in maintaining the integrity of the matrix tablet as well as the modified release coating on a tablet subjected to conventional storage conditions, as described further in example 3.
- the solid dosage forms of the present invention provide for zero-order release of the pharmaceutical agent upon dissolution.
- the fluid diffuses through the modified release coating, dissolving the hydrophilic pore-forming agent to form pores or channels in the modified release coating.
- the fluid continues to diffuse through the barrier coating (if present) and matrix core, dissolving the pharmaceutical agent embedded in the matrix core.
- the pharmaceutical agent travels through the pores in the modified release coating out of the dosage form.
- the matrix core includes a pharmaceutically active agent, a hydrophobic material, and optional fillers, release modifiers, lubricants, and glidants.
- the pharmaceutically active agent within the matrix core can be any water soluble pharmacologically active compound.
- active agents suitable in the present invention include antihistamines, antibiotics, antituberculosis agents, cholinergic agents, antimuscarinics, sympathomimetics, sympatholytic agents, autonomic drugs, iron preparations, haemostatics, cardiac drugs, antihypertensive agents, vasodilators, non-steroidal antiinflammatory agents, opiate agonists, anticonvulsants, tranquilizers, stimulants, barbiturates, sedatives, expectorants, antiemetics, gastrointestinal drugs, heavy metal antagonists, antithyroid agents, genitourinary smooth muscle relaxants and vitamins.
- Suitable water soluble actives include, but are not limited to, abacavir sulfate, acyclovir, aminocaproic acid, alendronate sodium, amitriptyline hydrochloride, amphetamine, acetaminophen, allopurinol, amoxicillin, atenolol, atropine sulfate, azithromycin, balsalazide, benzepril hydrochloride, bisoprolol fumarate, bupropion hydrochloride, buformin, calacyclovir, captopril, cefprozil, cetrizine hydrochloride, cimetidine, ciprofloxacin, clindamycin, chlorpheniramine maleate, chlorpromazine hydrochloride, clomipramine hydrochloride, clonidine hydrochloride, clopidogrel bisulfate, cloxacillin sodium, codeine phosphate, colchicines, cyclo
- the pharmaceutical agent is present in an amount from about 2 wt.% to about 25 wt.% of the total weight of the uncoated matrix core, preferably from about 4 wt.% to about 16 wt.%, and more preferably from about 5 wt.% to about 11 wt.%.
- the hydrophobic material within the matrix core acts as a release rate retarding agent.
- the hydrophobic material is any non-swellable hydrophobic material comprising at least one polymer.
- suitable hydrophobic materials include a glyceride (e.g., glyceryl behenate, glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate, glyceryl monostearate, glyceryl palmitostearate, or glyceryl triacetate), hydrogenated castor oil, a hydrogenated vegetable oil, a water insoluble cellulose (e.g., ethyl cellulose, cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose, cellulose diacetate, or cellulose triacetate), a wax or a wax-like substance (e.g., carnauba wax, cetyl
- the hydrophobic material comprises ethyl cellulose, such as AQUALONTM T10 EC, and/or glyceryl behenate, such as COMPRITOLTM 888 ATO.
- the hydrophobic material is present in an amount from about 10 wt.% to about 50 wt.% of the total weight of the uncoated matrix core, preferably from about 12 wt.% to about 40 wt.%, and more preferably from about 19 wt.% to about 30 wt.%.
- the matrix core can also include a release modifier to modify the release rate of the pharmaceutical agent from the matrix core.
- exemplary release modifiers include, but are not limited to, hydrophilic celluloses (e.g., hydroxypropyl cellulose, hypromellose, hypromellose phthalate, methyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, or hydroxymethyl propyl cellulose); saccharides (e.g., pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose, or sorbitol); polysaccharides (e.g., polydextrose, guar gum, hydroxypropyl guar, alginate, polysorbate, xanthan gum or carboxymethyl
- Preferred release modifiers include high viscosity hydroxypropyl cellulose (KLUCELTM HXF) and lower viscosity hydroxypropyl cellulose (KLUCELTM EF).
- the release modifier is present in an amount up to about 40 wt.%, from about 5 wt.% to about 20 wt.%, from about 3 wt.% to about 17 wt.% of the total weight of the uncoated matrix core, preferably from about 4 wt.% to about 14 wt.%, and more preferably from about 5 wt.% to about 10 wt.%.
- the release modifier is present in an amount from about 10 wt.% to about 17 wt.%.
- the matrix core of the solid dosage forms of the present invention can include at least one pharmaceutically acceptable filler as an excipient.
- fillers used herein means the fillers or binders which are used for ordinary pharmaceutical production, and includes excipients which facilitate the flow and compression of powdery materials and give the solid dosage forms strength.
- suitable fillers for use in the matrix core of the present invention: microcrystalline cellulose, sodium citrate, dicalcium phosphate, colloidal silicon dioxide, starches, lactose, sucrose, glucose, mannitol, and silicic acid, alginates, gelatin, polyvinylpyrrolidinone, lactitol, dextrose, acacia, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, starch, and pregelatinized starch, with microcrystalline cellulose, such as PROSOLVTM HD90, being preferred in some embodiments.
- the filler can be present in an amount up to about 75% of the total weight of the uncoated matrix core.
- the content of the filler in the matrix core can be increased or decreased based on various factors such as active agent load, active agent solubility, and desired release profile.
- the filler is generally present in an amount from about 50% to about 75%, preferably from about 50 wt.% to about 70 wt.%, and more preferably from about 50 wt.% to about 65 wt.% or even from about 50 wt.% to about 58 wt.%.
- the matrix core of the solid dosage form of the present invention can further include at least one pharmaceutically acceptable lubricant as an excipient.
- lubricant as used herein includes excipients that reduce friction, heat and wear when applied as a surface coating to moving parts within the equipment used to make the matrices, such as dies and punches.
- Suitable lubricants include, either individually or in combination, a glyceride (e.g., glyceryl behenate (e.g., CompritolTM 888 ATO), glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate glyceryl monostearate, glyceryl palmitostearate, glyceryl triacetate); stearic acid and salts thereof, including magnesium, calcium, aluminum, zinc, and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; DL-leucine; polyethylene glycol (e.g., CarbowaxTM 4000 and CarbowaxTM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
- a glyceride
- the lubricant is more preferably selected from the group consisting of stearic acid salts such as calcium stearate and magnesium stearate, stearic acid, sodium stearyl fumarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
- stearic acid salts such as calcium stearate and magnesium stearate, stearic acid, sodium stearyl fumarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
- Magnesium stearate is a particularly preferred lubricant.
- the amount of lubricant in the matrix core is from about 0.5 wt.% to about 5 wt.% of the total weight of the uncoated matrix core, preferably from about 0.5 wt.% to about 3 wt.%, and more preferably from about 1 wt.% to about 2 wt.%.
- the matrix core can also include a glidant to improve flow of the mixture through the hopper used in forming the matrices.
- Suitable glidants include colloidal silicon dioxide (such as Cab-O-SilTM, M5), aluminum silicate, talc, powdered cellulose, magnesium trisilicate, silicon dioxide, kaolin, glycerol monostearate, metal stearates such as magnesium stearate, titanium dioxide and starch.
- Colloidal silicon dioxide is a preferred glidant.
- the amount of glidant in the matrix core is from about 1 wt.% to about 10 wt.% of the total weight of the uncoated matrix core, preferably from about 2 wt.% to about 7 wt.%, and more preferably from about 2 wt.% to about 4 wt.%.
- excipients for use in the matrix core such as colorants, flavors, sweeteners and stabilizers, are known in the pharmaceutical art and can be used in compositions of the present invention.
- the matrix core comprises from about 2 to about 25 wt.% of the water soluble pharmaceutical agent, up to about 5 wt.% lubricant, up to about 75 wt.% filler, up to about 25 wt.% release modifier, and up to about 10 wt.% glidant.
- the matrix core comprises from about 12 to about 40 wt.% of the hydrophobic material, from about 4 to about 16 wt.% of the water soluble pharmaceutical agent, from about 0.5 to about 3 wt.% lubricant, from about 50 to about 70 wt.% filler, from about 5 to about 20 wt.% release modifier, and up to about 7 wt.% glidant.
- the matrix core comprises from about 19 to about 30 wt.% of the hydrophobic material, from about 5 to about 11 wt.% of the water soluble pharmaceutical agent, from about 1 to about 2 wt.% lubricant, from about 50 to about 58 wt.% filler, from about 10 to about 17 wt.% release modifier, and up to about 4 wt.% glidant.
- the barrier coating of the solid dosage form comprises a water soluble polymer and optional anti-tacking agents or optional viscosity enhancing agents.
- the water soluble polymer of the barrier coating can be any water soluble polymer and is preferably a highly water soluble polymer.
- Suitable materials for use as the barrier coating include hypromellose, hypromellose phthalate, methyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl hydroxyethyl cellulose, ethylhydroxy ethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, hydroxymethyl propyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, a polyalkylene oxide, a polyalkylene glycol, an acrylic acid polymer, a vinyl acetate copolymer, a polysaccharide, a methacrylic acid copolymer, or a maleic anhydride/methyl vinyl ether copolymer.
- the barrier coating contains hypromellose.
- the barrier coating is used in an amount which is a weight gain of from about 2.0 wt.% to about 6.0 wt.% of the total weight of the uncoated matrix core, preferably from about 3 wt.% to about 5 wt.%, and more preferably from about 3.5 wt.% to about 4.5 wt.%.
- the barrier coating may include an anti-tacking agent to reduce agglomeration of the coating during application.
- anti-tacking agents for use in the barrier coating include talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid, and mixtures thereof.
- the amount of anti-tacking agent in the barrier coating is from about 5 wt.% to about 50 wt.% based on the total weight of the barrier coating.
- excipients for use in the barrier coating such as viscosity modifiers, are known in the pharmaceutical art and can be used in compositions of the present invention.
- the modified release coating includes a hydrophobic polymer, a hydrophilic pore-forming agent, and optional plasticizers and anti-tacking agents. Any hydrophobic polymer can be used in the modified release coating of the solid dosage form. Non-swelling polymers are preferred.
- hydrophobic polymers suitable for use in the modified release coating in the present invention include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose, polyvinyl chloride, polyvinyl acetate, polymethylmethacrylate, polyethylacrylate, polyacrylates, polymethacrylates such as EudragitTM (an ammonio methacrylate copolymer available from Rohm Pharma, Darmstadt, Germany), polyvinylchloride, polyethylene, polypropylene, polyisobutylene, polytrimethylammonioethylmethacrylate or a block polymer or copolymer thereof.
- EudragitTM an ammonio methacrylate copolymer available from Rohm Pharma, Darmstadt, Germany
- the hydrophobic polymer is present in an amount from about 5 wt.% to about 70 wt.% of the total weight of the modified release coating, preferably from about 20 wt.% to about 60 wt.%, and more preferably from about 25 wt.% to about 55 wt.%.
- Ethyl cellulose is a preferred hydrophobic polymer for use in the modified release coating.
- Ethyl cellulose can be a standard ethyl cellulose dispersion that contains ethyl cellulose, a suitable plasticizer, and stabilizers.
- An example of a suitable grade of ethyl cellulose dispersion is available from Colorcon, Inc. of West Point, Pa., under the tradename SURELEASETM, which contains approximately 25% solids by weight.
- Any hydrophilic pore-forming agent can be used in the modified release coating and can be a solid or liquid.
- Suitable pore-forming agents include, but are not limited to, a polymer (e.g., polyvinylpyrrolidone, a polyalkylene oxide, or a polyalkylene glycol), a cellulose or a cellulose ether (e.g., hypromellose, hypromellose phthalate, methyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, or hydroxymethyl propyl cellulose), a protein, a protein derivative, a saccharide (e.g., pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose,
- the hydrophilic pore forming agent is present in an amount from about 30 wt.% to about 95 wt.% of the total weight of the modified release coating, preferably from about 40 wt.% to about 80 wt.%, and more preferably from about 45 wt.% to about 75 wt.%.
- the pore-forming agent is a hydroxyalkyl alkyl cellulose, carboxymethyl cellulose, or salt thereof, such as hydroxyethyl methyl cellulose, hypromellose, carboxymethyl cellulose, or sodium carboxymethyl cellulose.
- the water-soluble component is hypromellose, such as OPADRYTM (available from Colorcon, West Point, Pa.).
- the modified release coating may include an anti-tacking agent to reduce agglomeration of the coating during application.
- anti-tacking agents for use in the modified release coating include talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid, and mixtures thereof.
- the amount of anti-tacking agent in the modified release coating is from about 5 wt.% to about 50 wt.% based on the total weight of the modified release coating.
- the modified release coating includes SURELEASETM (available from Colorcon) as the hydrophobic polymer and OPADRYTM (available from Colorcon) as the pore-forming agent. Weight ratios of 70:30, 80:20, 90:10 and 95:5 of SURELEASETM to OPADRYTM were tested, but coatings with equal to or more than 80% SURELEASETM showed variable release for some coatings. When the cores are coated with ethyl cellulose and hypromellose in ratios less than 80:20, a desired drug release profile with zero-order characteristics is achieved.
- SURELEASETM available from Colorcon
- OPADRYTM available from Colorcon
- the modified release coating contains from about 5 to about 70 wt.% of the hydrophobic polymer, from about 30 to about 95 wt.% of the hydrophilic pore-forming agent, up to about 40 wt.% plasticizer, and up to 50 wt.% anti-tacking agent. In other instances, the modified release coating includes from about 20 to about 60 wt.% of the hydrophobic polymer, from about 40 to about 80 wt.% of the hydrophilic pore-forming agent, from about 20 to about 35 wt.% plasticizer, and up to 20 wt.% anti-tacking agent.
- the modified release coating comprises from about 25 to about 55 wt.% of the hydrophobic polymer, from about 45 to about 75 wt.% of the hydrophilic pore-forming agent, and from about 20 to about 30 wt.% plasticizer, and up to 10 wt.% anti-tacking agent.
- the weight ratio of the hydrophobic polymer to the hydrophilic pore-forming agent is from about 1:1 to about 9:1, about 1:1 to about 4:1, about 1:1 to about 3:1, and preferably from about 1.25:1 to about 2.33:1.
- Example 3 it was discovered that polymer coating of mixtures of hydrophobic ethyl cellulose and hydrophilic hypromellose polymers are susceptible to film cracking. This can result in changes in dissolution profile upon storage. Film cracking can be overcome by imparting flexibility to the modified release coating and/or by adding plasticizer. SURELEASETM and OPADRYTM both contain some plasticizer. However, an additional amount of at least about 4, 5, 6, 7, 8, 9 or 10 wt.% plasticizer or more is added to prevent the coating from cracking under storage conditions, as shown by the results of Example 3. Any plasticizer for tablet coatings can be used.
- plasticizers are triacetin, methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di( ⁇ -methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrace, diisobutyl adipate, dihexyl adipate, triethylene glycol di(2-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate), diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethyl stearate
- the plasticizer was triacetin.
- the amount of added plasticizer in the release coating is from about 3 wt.% to about 20 wt.% of the total weight of the modified release coating, preferably from about 4 wt.% to about 15 wt.%, and more preferably from about 5 wt.% to about 10 wt.%.
- the amount of total plasticizer in the release coating is from about 20 wt.% to about 40 wt.% of the total weight of the modified release coating, preferably from about 20 wt.% to about 35 wt.%, and more preferably from about 20 wt.% to about 30 wt.%.
- the solid dosage form of the invention can optionally include an overcoating to provide an initial dose burst of an active agent.
- the overcoating contains any pharmaceutically active agent, a water soluble polymer, an optional anti-tacking agent, an optional plasticizer, an optional stabilizer, and an optional viscosity enhancing agent.
- the overcoating if present, is applied to the modified release coated, optionally barrier coated matrix core tablet.
- active agents include any water insoluble drugs, as well as any water soluble drug such as those listed above with regard to the active agent of the matrix core. In some cases, a water soluble active agent is preferred in the overcoating.
- the pharmaceutically active agent within the overcoating is the same active agent as included in the matrix core. In other embodiments, the pharmaceutically active agent within the overcoating is different than the active agent as included in the matrix core.
- the active agent is not highly water soluble and forms a suspension rather than a solution with the water soluble polymer.
- the particle size of the active agent and any other undissolved components in such overcoating suspension can be in the micron range to minimize settling of these components in the suspension and to maintain a homogeneous suspension.
- the water soluble polymer of the overcoating can be any water soluble polymer and is preferably a highly water soluble polymer.
- Suitable materials for use in the overcoating include hypromellose, hypromellose phthalate, methyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl hydroxyethyl cellulose, ethylhydroxy ethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, hydroxymethyl propyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, a polyalkylene oxide, a polyalkylene glycol, an acrylic acid polymer, a vinyl acetate copolymer, a polysaccharide, a methacrylic acid copolymer, or a maleic anhydride/methyl vinyl ether copolymer.
- the overcoating contains hypromellose.
- the overcoating is used in an amount which is a weight gain of from about 2 wt.% to about 25 wt.% of the total weight of the overcoated solid dosage form, preferably from about 4 wt.% to about 12 wt.%, and more preferably from about 5 wt.% to about 6.5 wt.%.
- the overcoating may contain a plasticizer. Any plasticizer for tablet coatings can be used. Exemplary plasticizers are those described above for the overcoating. In some embodiments, the plasticizer is triacetin or polyethylene glycol. When present, the amount of plasticizer in the overcoating is from about 5 wt.% to about 30 wt.% of the total weight of the overcoating.
- the overcoating may include an anti-tacking agent to reduce agglomeration of the coating during application.
- anti-tacking agents for use in the overcoating include talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid, and mixtures thereof.
- the amount of anti-tacking agent in the overcoating is from about 5 wt.% to about 50 wt.% based on the total weight of the overcoating.
- the overcoating can include an optional stabilizer to minimize or prevent degradation of the pharmaceutically active agent in the overcoating.
- Any pharmaceutically acceptable compound which minimizes degradation of the pharmaceutically active agent in the overcoating can be used.
- an acidic compound such as hydrochloric acid or fumaric acid can be used to stabilize the active agent when the active agent is more stable in acidic pH.
- an acid can be used to stabilize methylphenidate.
- suitable stabilizers for the particular active agents of the dosage forms of the invention is from about 1 wt.% to about 10 wt.% based on the total weight of the overcoating.
- the overcoating may also include an optional viscosity enhancing agent to reduce settling of the active agent in the overcoat, particularly when the overcoating is applied as a suspension rather than as a solution.
- viscosity enhancing agents for use in the overcoating include a sugar (dextrose, glucose and sucrose), a cellulose derivative such as sodium or calcium carboxymethylcellulose and hydroxypropyl cellulose, a polysaccharide, a pectin, agar, carrageenan, a hydrophilic gum such as acacia gum, guar gum, arabic gum and xanthan gum, alginic acid, an alginate, dextran, a carbomer resin, and mixtures thereof.
- the amount of viscosity enhancing agent in the overcoating is from about 2 wt.% to about 20 wt.% based on the total weight of the overcoating.
- the drug release rate is no longer zero order when the same drug within the matrix core is used in the overcoating.
- the drug release rate of the drug within the matrix core is zero order, but the drug release rate of the drug in the overcoating is not zero order.
- the overcoating contains from about 25 wt.% to about 77 wt.% of the pharmaceutical agent, from about 23 wt.% to about 75 wt.% of the water soluble polymer, up to about 50 wt.% of the anti-tacking agent, up to about 10 wt.% of the stabilizer, and up to about 20 wt.% of the viscosity enhancing agent.
- the overcoating includes from about 36 wt.% to about 45 wt.% of the pharmaceutical agent, from about 55 wt.% to about 64 wt.% of the water soluble polymer, up to about 5 wt.% of the anti-tacking agent, up to about 1 wt.% of the stabilizer, and up to about 2 wt.% of the viscosity enhancing agent.
- the weight ratio of the water soluble polymer to the pharmaceutical agent in the overcoating is from about 0.3:1 to about 3.0:1, preferably from about 1.2:1 to about 1.8:1.
- the matrix core, overcoating, modified release coating and/or barrier coating can include additional conventional excipients known in the art.
- solid dosage forms can be provided exhibiting improved performance with respect to, among other properties, efficacy, bioavailability, clearance time, stability, safety, dissolution profile, disintegration profile and/or other pharmacokinetic, chemical and/or physical properties.
- the combination of excipients selected provides tablets that can exhibit improvement, among other properties, in dissolution profile, hardness, crushing strength, and/or friability.
- the solid dosage forms can be formulated into a variety of physical structures or forms, including tablets, lozenges and caplets. No specialized geometry of the matrix core is necessary in the present invention.
- the matrix core may be in any shape known in the pharmaceutical industry and suitable for drug delivery, such as in spherical, cylindrical, or conical shape. Tablets are preferred.
- the methylphenidate formulations of the present invention may be administered to children and adults and preferably have a duration of action of about 6 hours and not more than about 10 hours.
- the inventive methylphenidate formulation should be taken at breakfast time and is designed to eliminate the need for dosing at school or work during lunch time. If a patient requires more than 10 hours of treatment per day an additional dose of immediate release methylphenidate should be taken at dinner. If the patient requires 24 hour treatment an additional does of the inventive formulation should be given at dinner time.
- the solid dosage forms of the present invention are made by a simple method under ambient conditions without the use of expensive manufacturing equipment. Other methods, such as wet granulation, are more expensive, time consuming, involve more excipients, and require more capital equipment.
- the method provides ease of manufacture and drug release in a substantially linear fashion over an extended period of time.
- the method comprises mixing between about 10% and about 50% of the non-swellable hydrophobic material comprising at least one polymer, from about 2 to 25 wt.% of the water-soluble pharmaceutical agent, the optional filler, the optional release modifier, the optional lubricant, and the optional glidant to form a mixture, and compressing the mixture.
- the mixture comprises not more than about 9, 10, 11, 12 or 13 wt.% of the water soluble pharmaceutical agent.
- the mixture can be formed and/or compressed under ambient conditions. Any conventional method of direct compression is suitable for preparing the matrix core.
- the matrix core is coated with a water soluble polymer, optionally mixed with an anti-tacking agent, to form a barrier coating surrounding the matrix core. Coating methods are well known in the art. After the barrier coating has dried, it is coated with the modified release coating. Once the modified release coating has dried, the dosage form can be stored.
- the solid dosage form is capable of releasing the pharmaceutical agent at a zero order rate for a period of at least 4, 5, 6, 7, 8, 9 or 10 hours after administration to a subject.
- the modified release coated matrix core is coated with a mixture of the water soluble pharmaceutically active agent, the water soluble polymer, the optional anti-tacking agent, the optional stabilizer, and the optional viscosity enhancing agent, and dried. Conventional coating methods can be used.
- the overcoated dosage form can be stored.
- the pharmaceutical active agent is placed in a V-blender or like mixing apparatus with the hydrophobic material, optional filler, optional release modifier, optional lubricant, and optional glidant and mixed for several minutes under ambient conditions.
- the mixture is compressed using a Korsch PH 106 tablet press or other standard tabletting equipment under ambient conditions without use of heat or solvent to form the matrix core.
- the matrix core is then coated with the barrier coating and the modified release coating using a Vector Hi-coater or comparable coating apparatus.
- methylphenidate hydrochloride is placed in a V-blender with ethyl cellulose and silicified microcrystalline cellulose and mixed for five minutes. Thereafter, colloidal silicon dioxide is added as a glidant and the mixture is mixed for another five minutes.
- the mixture is compressed using a Korsch PH 106 tablet press under ambient conditions.
- the resulting matrix core is then coated with a hypromellose coating and a modified release coating containing hypromellose, ethyl cellulose, and optional triacetin using a Vector Hi-coater.
- Methylphenidate hydrochloride was placed in a V-blender with ethyl cellulose, hydroxypropyl cellulose and silicified microcrystalline cellulose and mixed for five minutes. Thereafter, magnesium stearate was added as a lubricant and the mixture was mixed for another five minutes. Then, the mixture was compressed using a Korsch PH 106 tablet press under ambient conditions to form a matrix core.
- the matrix core contained the ingredients in the table below.
- Methylphenidate HCl 21 Hydroxypropyl Cellulose (KLUCELTM HXF) 25 Ethyl cellulose (AQUALONTM T10 EC) 75 Silicified Microcrystalline Cellulose (PROSOLVTM HD90) 126.5 Magnesium Stearate 2.5 Total 250
- the methylphenidate hydrochloride was the water soluble pharmaceutical agent
- ethyl cellulose was the hydrophobic material
- high viscosity hydroxypropyl cellulose was the release modifier
- silicified microcrystalline cellulose was a filler
- magnesium stearate was used as a lubricant.
- the tablets were not coated.
- the release characteristics of the tablets were tested by placing tablets in 0.1 % formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, the amount of methylphenidate hydrochloride dissolved in each trial run was determined. The experimental results are depicted in Figure 1A and were determined via UV spectroscopy at 200 nm.
- Figure 1B is a plot of ln (100-%methylphenidate hydrochloride dissolved) as a function of time and indicates first order drug release for the uncoated matrix core tablets.
- the matrix cores were coated with a modified release coating comprising 70% SURELEASETM and 30% OPADRYTM (% w/w solid content).
- the tablets were coated with varying quantities of coating, up to 8 wt.% based on weight gain of the tablet, and some tablets were not coated.
- the preferred amount of coating to achieve a zero-order release profile was experimentally determined by placing tablets in 0.1% formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used.
- Figure 2A is a plot of ln (100-%methylphenidate hydrochloride dissolved) as a function of time and indicates zero order drug release for the coated tablets.
- a matrix core was produced according to the method of production of reference example 1.
- the matrix core contained the ingredients in the table below.
- Ingredient Weight (mg) Methylphenidate HCl 21 Glyceryl Behenate (COMPRITOLTM 888 ATO) 31.25 Hydroxypropyl Cellulose (KLUCELTM EF) 12.25 Silicified microcrystalline Cellulose (PROSOLYTM HD90) 185.25 Colloidal Silicon Dioxide 5.0 Total 255
- the methylphenidate hydrochloride was the water soluble pharmaceutical agent, low viscosity hydroxypropyl cellulose was used as a release modifier, glyceryl behenate was added as both the hydrophilic material and as a lubricant, silicified microcrystalline cellulose was a filler, and colloidal silicon dioxide was used as a glidant.
- the tablets were not coated.
- the release characteristics of the tablets were tested by placing tablets in 0.1 % formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, the amount of methylphenidate hydrochloride dissolved in each trial run was determined. The experimental results are depicted in Figure 3 , and were determined via UV spectroscopy at 200 nm.
- the matrix cores were coated with a coating comprising 70% SURELEASETM and 30% OPADRYTM (% w/w solid content).
- the tablets were coated with varying quantities of coating, up to 8 wt.% based on weight gain of the tablet, and some tablets were not coated.
- the preferred amount of coating to achieve a zero-order release profile was experimentally determined by placing tablets in 0.1 % formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used.
- Figure 4A is a plot of ln (100-%methylphenidate hydrochloride dissolved) as a function of time and indicates zero order drug release for the 6% and 8% coated tablets.
- the matrix cores of reference example 1 were formed, they were coated with a coating comprising 80% SURELEASETM and 20% OPADRYTM (% w/w solid content).
- the tablets were coated with varying quantities of coating, up to 8 wt.% based on weight gain of the tablet, and some tablets were not coated.
- the preferred amount of coating to achieve a zero-order release profile was experimentally determined by placing tablets in 0.1% formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used.
- Figure 5A is a plot of ln (100-%methylphenidate hydrochloride dissolved) as a function of time and indicates zero order drug release for the 4% coated tablets. It is expected that the tablets having a 6% or 8% polymer coating would have exhibited a zero-order release profile if the testing were extended beyond 12 hours.
- the matrix cores of reference example 1 were formed, they were coated with a coating comprising 95% SURELEASETM and 5% OPADRYTM (% w/w solid content).
- the tablets were coated with varying quantities of coating, up to 6 wt.% based on weight gain of the tablet, and some tablets were not coated.
- the preferred amount of coating to achieve a zero-order release profile was experimentally determined by placing tablets in 0.1% formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used.
- Matrix core tablets were prepared as in reference Example 1. These were coated with a mixture of ethyl cellulose and hypromellose in ratio of 70:30 w/w. The tablets were placed in an oven at a temperature of 50°C for up to 7 days. The dissolution profiles of tablets before and after oven-heating were compared.
- the uncoated matrix tablets provided a dissolution profile with first-order release kinetics.
- these matrix tablets were coated to a total weight gain of at least 6 wt.%, a slower drug dissolution rate with zero-order characteristics was observed.
- the coated tablets were placed in an oven at 50°C, the dissolution rate increased and the shape of the profile reverted to first-order kinetics. This was attributable to the observed rupture of the polymer coating near the edges of the central band of the tablets.
- the shape of drug release profile of coated tablets assumed that of core matrices.
- the breaking of the polymer film can be a result of one or more of the following: (i) brittleness of the hybrid polymer film; (ii) expansion of tablet core during oven-heating and/or in-vitro dissolution; and (iii) non-uniformity of polymer layer thickness due to preferential coating on the top and bottom faces of the tablet surface.
- This effect of on the dissolution profile was eliminated by optimizing the level of plasticizer, which increased the film flexibility. Coating thickness uniformity was improved by proper design of tablet tooling.
- Another means of preventing such cracking is by applying a barrier coating prior to the application of the modified release coating.
- the same coating apparatus that was used in the prior examples was used to apply the barrier coating and then the modified release coating.
- the tablets were coated with 4 wt.% barrier coating, based on the weight gain of the matrix core, and either 4 wt.% or 6 wt.% of modified release coating, based on weight gain of the tablet, and some tablets were not coated.
- the 6% modified release coated tablets were either uncured (i.e., no 50°C heating), cured at 50°C for 1 day, or cured at 50°C for 7 days.
- the preferred amount of coating to achieve a zero-order release profile was experimentally determined by placing tablets in 0.1 % formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, the amount of methylphenidate hydrochloride dissolved in each trial run was determined. The experimental results are depicted in Figures 7 and 8 , and were determined via UV spectroscopy at 200 nm. Visual observation revealed that the coating remained intact during the entire dissolution process.
- tablets having a matrix core including ethyl cellulose and hypromellose in a ratio of 1:3, a modified release coating and a barrier coating were prepared as described above, except that the modified release 6% coating included ethyl cellulose, triacetin, and hypromellose in a ratio of 70:3.5:26.5.
- the results are depicted in Figure 9 .
- the addition of a plasticizer to the modified release coating increased the flexibility of the coating on the tablets cured at 50°C.
- a matrix core was produced according to the method of production of reference example 1.
- the matrix core contained the ingredients in the table below.
- Glyceryl Behenate (COMPRITOLTM 888 ATO) 0 75
- Ethyl Cellulose (AQUALONTM T10 EC) 135
- Hydroxypropyl Cellulose (KLUCELTM HXF) 45
- Hydroxypropyl Cellulose (KLUCELTM EF) 0 15 Silicified Microcrystalline Cellulose (PROSOLVTM HD90) 90 183
- Friability of the uncoated tablets was tested using a USP friability tester at 100 revolutions at different hardness values for both formulations. The results are shown in Figures 10 and 11 , wherein “kP” indicates kilo pounds, a unit of force for expressing hardness or crushing strength of pharmaceutical tablets, and “kN” indicates kilo Newtons, a unit of compression force.
- Uncoated matrix core tablets prepared at various hardness and under various compression forces were also placed in 0.1% formic acid aqueous solution (pH 2.6). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, the amount of methylphenidate hydrochloride dissolved in each trial run was determined. The experimental results are depicted in Figures 12 and 13 , and were determined via UV spectroscopy at 200 nm.
- Uncoated matrix cores were prepared as in reference example 1 to contain the following ingredients. Upon dissolution, the matrix cores showed similar dissolution to that reported for other matrix cores of the invention.
- Ingredient Formula I Weight (mg) Formula II Weight (mg) Methylphenidate HCl 14 28 Ethyl Cellulose (AQUALONTM T10 EC) 75 75 Hydroxypropyl Cellulose (KLUCELTM HXF) 25 25 Hydroxypropyl Cellulose (KLUCELTM EF) 0 40 Silicified Microcrystalline Cellulose (PROSOLVTM HD90) 133.5 228 Magnesium Stearate 2.5 4 Total 250 400
- Matrix core tablets including a barrier coating were prepared and then coated with a modified release coating as described in the examples and reference examples above. These tablets were then overcoated with an overcoat solution and dried. The overcoated tablets were further coated with a colorant coating and dried to form the final tablet.
- the formulations were prepared to contain the ingredients as shown below: Ingredient Formula C Weight (mg) Formula D Weight (mg) Matrix Core Methylphenidate HCl 21 21 Hydroxypropyl Cellulose (KLUCELTM HXF) 25 25 Ethyl Cellulose (AQUALONTM T10 EC) 75 75 Silicified Microcrystalline Cellulose (PROSOLVTM HD90) 126.5 126.5 Magnesium Stearate 2.5 2.5 Barrier Coating OPADRYTM CLEAR 10.4 10.4 Modified Release Coating SURELEASETM CLEAR 11.6 20.3 Triacetin 0.6 1.0 OPADRYTM CLEAR 4.4 7.7 Overcoating Methylphenidate HCl 6 6 OPADRYTM CLEAR 9.8 10.5 Color coating OPADRYTM II GRAY 9.1 9.5 Total 301.9 315.4 Ingredient Formula E Weight (mg) Formula F Weight (mg) Matrix Core Methylphenidate HCl 42 42 Hydroxypropyl Cellulose (KLUCELTM HXF
- the tablets of Formulae E and F and of Formula C were placed in 0.1% hydrochloric acid aqueous solution (pH 3.0). USP paddle apparatus was used at 50 rpm to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours, the amount of methylphenidate hydrochloride dissolved in each trial run was determined. The experimental results are depicted in Figures 14 and 15 , respectively, and were determined via UV spectroscopy at 200 nm.
Claims (15)
- Eine feste Dosierform, umfassend:Einen Matrixkern, welcher zwischen etwa 10% und etwa 50% eines nicht quellbaren hydrophoben Materials enthält, enthaltend wenigstens ein Polymer und ein wasserlösliches pharmazeutisches Mittel; undeine modifizierte Freisetzungsbeschichtung, welche den Matrixkern umgibt, wobei die modifizierte Freisetzungsbeschichtung ein hydrophobes Polymer und ein hydrophiles porenbildendes Mittel enthält;eine wasserlösliche Barrierebeschichtung zwischen der modifizierten Freisetzungsbeschichtung und dem Matrixkern, so dass die Barrierebeschichtung den Matrixkern umgibt und die modifizierte Freisetzungsbeschichtung die Barrierebeschichtung umgibt;wobei die feste Dosierform in der Lage ist, das pharmazeutische Mittel mit einer Freisetzungsgeschwindigkeit nullter Ordnung während einer Dauer von wenigstens vier Stunden nach Verabreichung an einen Probanden freizusetzen.
- Die Dosierform nach Anspruch 1, wobei die feste Dosierform in der Lage ist, das pharmazeutische Mittel mit einer Freisetzungsgeschwindigkeit nullter Ordnung innerhalb von etwa sechs bis etwa zehn Stunden nach Verabreichung an einen Probanden freizusetzen.
- Die feste Dosierform nach irgendeinem der vorhergehenden Ansprüche, wobei das wasserlösliche pharmazeutische Mittel umfasst: Abacavirsulfat, Acyclovir, Aminocapronsäure, Alendronat-Natrium, Amitriptylinhydrochlorid, Amphetamin, Acetaminophen, Allopurinol, Amoxicillin, Atenolol, Atropinsulfat, Azithromycin, Balsalazid, Benzeprilhydrochlorid, Bisoprololfumarat, Bupropionhydrochlorid, Buformin, Calacyclovir, Captopril, Cefprozil, Cetrizinhydrochlorid, Cimetidin, Ciprofloxacin, Clindamycin, Chlorpheniraminmaleat, Chlorpromazinhydrochlorid, Clomipraminhydrochlorid, Clonidinhydrochlorid, Clopidogrelbisulfat, Cloxacillin-Natrium, Codeinphosphat, Colchicin, Cyclophosphamid, Diethylcarbamazincitrat, Diltiazem, Doxycyclin, Doxepin, DL-Methionin, Eprosartan, Ethembutolhydrochlorid, Ethosuximid, Erythromycin, Fexofenadin, Eisensulfat, Fluoxetinhydrochlorid, Fluvastatin, Fosonopril-Natrium, Gabapentin, Hydralazinhydrochlorid, Hydrocodonbitartrat, Hydroxyzinhydrochlorid, Hydroxyharnstoff, Indinavirsulfat, Isoniazid, Isosorbidmononitrat, Lactobionat, Lamivudin, Levamisolhydrochlorid, Levofloxacin, Lisinopril, Losartan-Kalium, Metforminhydrochlorid, Methylphenidat, Methylphenidathydrochlorid, Metoprololtartrat, Minocyclinhydrochlorid, Montelukast-Natrium, Naxopren-Natrium, Neostigminbromid, Nicotinamid, Niacin, Nifurtimox, Nortriptylinhydrochlorid, Olanzepin, Oxybutyninchlorid, Penicillamin, Penicillin V-Kalium, Phenytoin-Natrium, Phenformin, Pramipexol, Pravastatin-Natrium, Kaliumchlorid, Primaquinphosphat, Promethazin, Promethazinhydrochlorid, Propanololhydrochlorid, Propoxyphenhydrochlorid, Pseudoephedrinhydrochlorid, Pyridostigminbromid, Pyridoxinhydrochlorid, Quniaprilhydrochlorid, Quetiapin, Ramipril, Ranitidinhydrochlorid, Reboxetin, Risedronat-Natrium, Rosiglitazonmaleat, Sildenafil, Natriumvalproat, Salbutamolsulfat, Stavudin, Sumanirol, Sumatriptansuccinat, Terazosinhydrochlorid, Tetracyclinhydrochlorid, Timololmaleat, Tramadolhydrochlorid, Valacyclovirhydrochlorid, Vancomycin, Venlafaxinhydrochlorid, Verapamilhydrochlorid, Warfarin-Natrium oder Kombinationen davon.
- Die Dosierform gemäß irgendeinem der vorhergehenden Ansprüche, wobei der Matrixkern von etwa 2 bis etwa 25 Gew.-% wasserlösliches pharmazeutisches Mittel, bis zu etwa 5 Gew.-% Schmiermittel, bis zu etwa 75 Gew.-% Füllstoff, bis zu etwa 25 Gew.-% Freisetzungsmodifikator und bis zu etwa 10 Gew.-% Gleitmittel enthält.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche, wobei die modifizierte Freisetzungsbeschichtung ferner einen Weichmacher enthält.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche, wobei die modifizierte Freisetzungsbeschichtung von etwa 5 bis etwa 70 Gew.-% hydrophobes Polymer, von etwa 30 bis 95 Gew.-% hydrophiles porenbildendes Mittel, bis zu etwa 40 Gew.-% Weichmacher und bis zu 50 Gew.-% Antihaftmittel enthält.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche, wobei das Gewichtsverhältnis des hydrophoben Polymers zu hydrophilem porenbildendem Mittel von etwa 1:1 bis etwa 9:1 beträgt.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche, wobei die Barrierebeschichtung ein wasserlösliches Polymer enthält.
- Die Dosierform nach Anspruch 8, wobei das wasserlösliche Polymer umfasst:Hypromellose, Hypromellosephtalat, Methylcellulose, Carboxymethylcellulose-Natrium, Hydroxyethylcellulose, Hydroxypropylcellulose, Carboxymethylhydroxyethylcellulose, Ethylhydroxyethylcellulose, Ethylmethylcellulose, Hydroxyethylmethylcellulose, Hydroxymethylcellulose, Hydroxymethylpropylcellulose, Polyvinylalkohol, Polyvinylpyrrolidon, ein Polyalkylenoxid, ein Polyalkylenglykol, ein Acrylsäurepolymer, ein Vinylacetatcopolymer, ein Polysaccharid, ein Methacrylsäurecopolymer, oder ein Maleinanhydridmethylvinylethercopolymer.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche, wobei die Barrierebeschichtung mit eineem Gewichtszuwachs von etwa 2 bis etwa 6 Gew.-%, basierend auf dem Gesamtgewicht des Matrixkerns, zu Buche schlägt.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche, welche ferner einen Überzug umfasst, welcher die modifizierte Freisetzungsbeschichtung umgibt, wobei der Überzug ein pharmazeutisches Mittel und ein wasserlösliches Polymer enthält.
- Die Dosierform nach irgendeinem der vorhergehenden Ansprüche in Form einer Tablette.
- Ein Verfahren zum Herstellen einer festen Dosierform, welches umfasst:Mischen zwischen ungefähr 10% und etwa 50% eines nicht quellbaren hydrophoben Materials, welches wenigstens ein Polymer enthält, von etwa 2 bis 25 Gew.-% eines wasserlöslichen pharmazeutischen Mittels, eines optionalen Füllstoffs, eines optionalen Schmiermittels und eines optionalen Gleitmittels, um eine Mischung zu bilden;Komprimieren der Mischung, um einen Matrixkern zu bilden;Beschichten des Matrixkerns, um eine Barrierebeschichtung zu bilden, welche den Matrixkern umgibt;Trocknen der Barrierebeschichtung;Beschichten des barrierebeschichteten Matrixkerns mit einer modifizierten Freisetzungsbeschichtung; undTrocknen der modifizierten Freisetzungsbeschichtung, um die feste Dosierform zu bilden, wobei die Barrierebeschichtung ein wasserlösliches Polymer enthält, die modifizierte Freisetzungsbeschichtung ein hydrophobes Polymer und ein hydrophiles porenbildendes Mittel enthält und die feste Dosierform in der Lage ist, das pharmazeutische Mittel mit einer Geschwindigkeit nullter Ordnung für eine Dauer von wenigstens vier Stunden nach Verabreichung an einen Probanden freizusetzen.
- Das Verfahren nach Anspruch 13, wobei das Verfahren weiter die Schritte des Beschichtens der festen Dosierform mit einem Überzug umfasst, wobei der Überzug ein wasserlösliches Polymer und ein pharmazeutisches Mittel enthält.
- Das Verfahren nach Anspruch 13 oder 14, wobei die feste Dosierform nach irgendeinem der Ansprüche 1 bis 12 hergestellt wird.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79888906P | 2006-05-09 | 2006-05-09 | |
US85622606P | 2006-11-01 | 2006-11-01 | |
EP07776913A EP2020995A2 (de) | 2006-05-09 | 2007-05-09 | Feste darreichungsformen mit modifizierter freisetzung nullter ordnung |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07776913.1 Division | 2007-05-09 | ||
EP07776913A Division EP2020995A2 (de) | 2006-05-09 | 2007-05-09 | Feste darreichungsformen mit modifizierter freisetzung nullter ordnung |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2457562A1 EP2457562A1 (de) | 2012-05-30 |
EP2457562B1 true EP2457562B1 (de) | 2017-04-05 |
Family
ID=38659385
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07776913A Ceased EP2020995A2 (de) | 2006-05-09 | 2007-05-09 | Feste darreichungsformen mit modifizierter freisetzung nullter ordnung |
EP12156178.1A Active EP2457562B1 (de) | 2006-05-09 | 2007-05-09 | Feste Darreichungsformen mit modifizierter Freisetzung nullter Ordnung |
EP12156190.6A Active EP2457563B1 (de) | 2006-05-09 | 2007-05-09 | Feste Darreichungsformen mit modifizierter Freisetzung nullter Ordnung |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07776913A Ceased EP2020995A2 (de) | 2006-05-09 | 2007-05-09 | Feste darreichungsformen mit modifizierter freisetzung nullter ordnung |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP12156190.6A Active EP2457563B1 (de) | 2006-05-09 | 2007-05-09 | Feste Darreichungsformen mit modifizierter Freisetzung nullter Ordnung |
Country Status (9)
Country | Link |
---|---|
US (2) | US20090110728A1 (de) |
EP (3) | EP2020995A2 (de) |
JP (1) | JP2009536654A (de) |
AU (1) | AU2007249947B2 (de) |
CA (1) | CA2651798C (de) |
ES (2) | ES2626632T3 (de) |
MX (2) | MX350380B (de) |
PL (2) | PL2457563T3 (de) |
WO (1) | WO2007133583A2 (de) |
Families Citing this family (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
EP1429739A1 (de) | 2001-09-21 | 2004-06-23 | Egalet A/S | Polymer-freigabe-system |
EP2301526B1 (de) | 2003-03-26 | 2016-03-23 | Egalet Ltd. | System zur kontrollierten Freisetzung von Morphin |
WO2005011707A1 (en) | 2003-07-25 | 2005-02-10 | Warner Chilcott Company, Inc. | A doxycycline metal complex in a solid dosage form |
CN101128206A (zh) * | 2005-01-21 | 2008-02-20 | 沃纳奇尔科特公司 | 固体剂型形式的四环素类金属络合物 |
US20100104621A1 (en) * | 2007-02-21 | 2010-04-29 | Connected Health Systems, Llc | Treating adhd and other diseases involving inflammation |
US8821928B2 (en) | 2007-06-04 | 2014-09-02 | Egalet Ltd. | Controlled release pharmaceutical compositions for prolonged effect |
US20100172991A1 (en) * | 2007-06-08 | 2010-07-08 | Henry Joseph Horacek | Extended Release Formulation and Methods of Treating Adrenergic Dysregulation |
MX2009013384A (es) * | 2007-06-08 | 2010-01-25 | Addrenex Pharmaceuticals Inc | Formulacion de liberacion extendida, y metodo para tratar disregulacion adrenergica. |
US20090246276A1 (en) * | 2008-01-28 | 2009-10-01 | Graham Jackson | Pharmaceutical Compositions |
WO2010001413A2 (en) | 2008-07-01 | 2010-01-07 | Lupin Limited | Sustained release pharmaceutical compositions comprising quetiapine |
DE102008046650A1 (de) | 2008-09-10 | 2010-03-11 | Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg | Quetiapin enthaltende Retardtablette |
US20100151020A1 (en) * | 2008-12-16 | 2010-06-17 | Vered Rosenberger | Drug delivery system for zero order, zero order biphasic, ascending or descending drug delivery of methylphenidate |
KR101699912B1 (ko) | 2009-01-09 | 2017-01-25 | 포워드 파마 에이/에스 | 1종 이상의 푸마르산 에스테르를 침식 매트릭스에 함유하는 제제 |
EP2393484A1 (de) | 2009-02-06 | 2011-12-14 | Egalet Ltd. | Gegen missbrauch durch alkoholeinnahme widerstandsfähige zusammensetzung mit unmittelbarer freisetzung |
NZ603579A (en) | 2009-06-24 | 2014-02-28 | Egalet Ltd | Controlled release formulations |
EP2575780A1 (de) | 2010-05-24 | 2013-04-10 | Lupin Limited | Pramipexolformulierung mit verlängerter freisetzung |
DE102010033527A1 (de) | 2010-08-05 | 2012-02-09 | Acino Pharma Ag | Quetiapin-Tabletten |
TR201008261A1 (tr) | 2010-10-08 | 2012-04-24 | Sanovel İlaç San. Ve Ti̇c. A.Ş. | Kontrollü salım gerçekleştiren ketiapin formülasyonları |
AU2011325371A1 (en) * | 2010-10-21 | 2013-05-02 | Galderma S.A. | Sustained-release tablet and process for preparing the same |
WO2012052479A2 (en) | 2010-10-21 | 2012-04-26 | Galderma S.A. | Brimonidine gel compositions and methods of use |
CN103370058A (zh) | 2010-12-22 | 2013-10-23 | 普渡制药公司 | 包覆的抗篡改控制释放剂型 |
CN107412173A (zh) | 2010-12-23 | 2017-12-01 | 普渡制药公司 | 抗篡改固体口服剂型 |
PT2663294E (pt) | 2011-01-11 | 2016-01-25 | Capsugel Belgium Nv | Novas cápsulas duras contendo pululano |
US10905652B2 (en) | 2011-03-23 | 2021-02-02 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8916588B2 (en) | 2011-03-23 | 2014-12-23 | Ironshore Pharmaceuticals & Development, Inc. | Methods for treatment of attention deficit hyperactivity disorder |
US9119809B2 (en) | 2011-03-23 | 2015-09-01 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
WO2012129551A1 (en) * | 2011-03-23 | 2012-09-27 | Ironshore Pharmaceuticals & Development, Inc. | Methods and compositions for treatment of attention deficit disorder |
US11241391B2 (en) | 2011-03-23 | 2022-02-08 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US8927010B2 (en) | 2011-03-23 | 2015-01-06 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9603809B2 (en) | 2011-03-23 | 2017-03-28 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US10292937B2 (en) | 2011-03-23 | 2019-05-21 | Ironshore Pharmaceuticals & Development, Inc. | Methods of treatment of attention deficit hyperactivity disorder |
US9283214B2 (en) | 2011-03-23 | 2016-03-15 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
US9498447B2 (en) | 2011-03-23 | 2016-11-22 | Ironshore Pharmaceuticals & Development, Inc. | Compositions for treatment of attention deficit hyperactivity disorder |
CN109908099B (zh) | 2011-05-13 | 2021-10-29 | Eb Ip希博里塔布斯有限责任公司 | 药物递送系统 |
US9119793B1 (en) | 2011-06-28 | 2015-09-01 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for doxycycline |
JP5976657B2 (ja) | 2011-09-30 | 2016-08-24 | 持田製薬株式会社 | 易服用性固形製剤 |
DE102011115690A1 (de) | 2011-10-11 | 2013-04-11 | Acino Pharma Ag | Quetiapin enthaltende Formulierungen |
FR2986431B1 (fr) * | 2012-02-03 | 2017-03-17 | Servier Lab | Composition pharmaceutique a liberation prolongee de trimetazidine, son procede de fabrication et son utilisation dans des traitements therapeutiques |
EP4233915A3 (de) * | 2012-02-08 | 2023-09-20 | Supernus Pharmaceuticals, Inc. | Modifizierte freisetzungsformulierungen von viloxazin |
EA201590165A1 (ru) | 2012-07-06 | 2015-08-31 | Эгалет Лтд. | Сдерживающие злоупотребление фармацевтические композиции для контролируемого высвобождения |
PL2822541T3 (pl) | 2012-09-10 | 2019-02-28 | Pharmathen S.A. | Kompozycja farmaceutyczna zawierająca nietypowy środek przeciwpsychotyczny i sposób jej wytwarzania |
MX2015010041A (es) | 2013-02-05 | 2015-10-30 | Purdue Pharma Lp | Formulacion farmaceuticas resistentes a la alteracion. |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10842802B2 (en) | 2013-03-15 | 2020-11-24 | Medicis Pharmaceutical Corporation | Controlled release pharmaceutical dosage forms |
CN104069502B (zh) * | 2013-03-29 | 2018-02-16 | 北京罗诺强施医药技术研发中心有限公司 | 复合骨架材料及其药物组合物 |
AU2014306759B2 (en) | 2013-08-12 | 2018-04-26 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
WO2015095391A1 (en) | 2013-12-17 | 2015-06-25 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
EP3169315B1 (de) | 2014-07-17 | 2020-06-24 | Pharmaceutical Manufacturing Research Services, Inc. | Missbrauchssichere flüssigkeitsfülldosierform mit unmittelbarer freisetzung |
US20160106737A1 (en) | 2014-10-20 | 2016-04-21 | Pharmaceutical Manufacturing Research Services, Inc. | Extended Release Abuse Deterrent Liquid Fill Dosage Form |
ES2929218T3 (es) * | 2015-01-12 | 2022-11-28 | Enteris Biopharma Inc | Formas farmacéuticas orales sólidas |
CN105982861B (zh) * | 2015-02-11 | 2020-04-14 | 北京科信必成医药科技发展有限公司 | 一种阿奇霉素无水吞服掩味颗粒剂 |
MX2018007977A (es) | 2015-12-31 | 2018-11-09 | Cadila Healthcare Ltd | Forma farmaceutica osmotica de liberacion extendida que contiene una carga de clorhidrato de metilfenidato alta. |
ES2641308B1 (es) * | 2016-05-05 | 2018-09-11 | Products & Technology, S.L. | Comprimidos de metilfenidato de liberación retardada |
JP2018095566A (ja) * | 2016-12-08 | 2018-06-21 | アサヒグループ食品株式会社 | 水溶性機能性原料含有組成物、ソフトカプセル、及びソフトカプセルにおける水溶性機能性原料の減成抑制方法 |
AU2018251256B2 (en) | 2017-04-14 | 2023-10-05 | Capsugel Belgium Nv | Pullulan capsules |
JP7222911B2 (ja) | 2017-04-14 | 2023-02-15 | カプスゲル・ベルギウム・ナムローゼ・フェンノートシャップ | プルランを作製する方法 |
CN110025570A (zh) * | 2019-05-25 | 2019-07-19 | 陕西中医药大学 | 新型中药蜂蜡块 |
CN110585154B (zh) * | 2019-10-17 | 2021-07-02 | 武汉光谷亚太医药研究院有限公司 | 一种琥珀酸美托洛尔微丸压片的方法 |
WO2022241255A1 (en) * | 2021-05-14 | 2022-11-17 | Ocumedic, Inc. | Extended-wear silicone hydrogel contact lenses and uses thereof |
US20230240998A1 (en) * | 2021-12-22 | 2023-08-03 | Hikma Pharmaceuticals Usa Inc. | Tofacitinib extended release formulations |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2887440A (en) * | 1957-08-12 | 1959-05-19 | Dow Chemical Co | Enteric coating |
US4309405A (en) * | 1979-08-09 | 1982-01-05 | American Home Products Corporation | Sustained release pharmaceutical compositions |
US4610870A (en) * | 1984-10-05 | 1986-09-09 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US5407686A (en) * | 1991-11-27 | 1995-04-18 | Sidmak Laboratories, Inc. | Sustained release composition for oral administration of active ingredient |
US6673367B1 (en) * | 1998-12-17 | 2004-01-06 | Euro-Celtique, S.A. | Controlled/modified release oral methylphenidate formulations |
US6500459B1 (en) * | 1999-07-21 | 2002-12-31 | Harinderpal Chhabra | Controlled onset and sustained release dosage forms and the preparation thereof |
US7674480B2 (en) * | 2000-06-23 | 2010-03-09 | Teva Pharmaceutical Industries Ltd. | Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition |
US7094469B2 (en) * | 2001-08-28 | 2006-08-22 | Mykrolis Corporation | Porous or non-porous substrate coated with an immobilized polymeric composition having sulfonyl groups and hydrophilic functional groups and process |
WO2003053402A1 (en) * | 2001-12-20 | 2003-07-03 | Pharmacia Corporation | Zero-order sustained released dosage forms and method of making the same |
KR100540035B1 (ko) * | 2002-02-01 | 2005-12-29 | 주식회사 태평양 | 다단계 경구 약물 방출 제어 시스템 |
US20040241234A1 (en) * | 2003-06-02 | 2004-12-02 | Alpharma, Inc. | Controlled release press-coated formulations of water-soluble active agents |
EP1663167A1 (de) * | 2004-07-26 | 2006-06-07 | Teva Pharmaceutical Industries Ltd | Dosierformen mit einer tablette mit enterisch beschichtetem kern |
BRPI0513848A (pt) * | 2004-08-13 | 2008-05-20 | Boehringer Ingelheim Int | formulação de pélete de liberação prolongada contendo pramipexol ou um sal farmaceuticamente aceitável deste, método para fabricação da mesma e uso desta |
-
2007
- 2007-05-09 MX MX2013009354A patent/MX350380B/es unknown
- 2007-05-09 ES ES12156178.1T patent/ES2626632T3/es active Active
- 2007-05-09 MX MX2008014059A patent/MX2008014059A/es active IP Right Grant
- 2007-05-09 CA CA2651798A patent/CA2651798C/en active Active
- 2007-05-09 JP JP2009509831A patent/JP2009536654A/ja active Pending
- 2007-05-09 EP EP07776913A patent/EP2020995A2/de not_active Ceased
- 2007-05-09 ES ES12156190.6T patent/ES2627127T3/es active Active
- 2007-05-09 PL PL12156190T patent/PL2457563T3/pl unknown
- 2007-05-09 US US12/299,944 patent/US20090110728A1/en not_active Abandoned
- 2007-05-09 EP EP12156178.1A patent/EP2457562B1/de active Active
- 2007-05-09 PL PL12156178T patent/PL2457562T3/pl unknown
- 2007-05-09 AU AU2007249947A patent/AU2007249947B2/en active Active
- 2007-05-09 WO PCT/US2007/011186 patent/WO2007133583A2/en active Application Filing
- 2007-05-09 EP EP12156190.6A patent/EP2457563B1/de active Active
-
2019
- 2019-08-01 US US16/529,323 patent/US20190358164A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Publication number | Publication date |
---|---|
CA2651798C (en) | 2015-07-21 |
EP2020995A2 (de) | 2009-02-11 |
ES2627127T3 (es) | 2017-07-26 |
EP2457562A1 (de) | 2012-05-30 |
PL2457563T3 (pl) | 2017-09-29 |
CA2651798A1 (en) | 2007-11-22 |
WO2007133583A3 (en) | 2008-05-22 |
ES2626632T3 (es) | 2017-07-25 |
WO2007133583A2 (en) | 2007-11-22 |
US20090110728A1 (en) | 2009-04-30 |
AU2007249947A1 (en) | 2007-11-22 |
PL2457562T3 (pl) | 2017-09-29 |
MX2008014059A (es) | 2008-11-14 |
EP2457563B1 (de) | 2017-03-22 |
US20190358164A1 (en) | 2019-11-28 |
MX350380B (es) | 2017-09-05 |
JP2009536654A (ja) | 2009-10-15 |
EP2457563A1 (de) | 2012-05-30 |
AU2007249947B2 (en) | 2013-03-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20190358164A1 (en) | Zero-order modified release solid dosage forms | |
JP6359022B2 (ja) | ヒドロモルホンおよびナロキソンを含む医薬組成物 | |
AU2006228525A1 (en) | Controlled absorption of statins in the intestine | |
JP2013504562A (ja) | アルコールで誘発される用量ダンピングを低減するための医薬組成物 | |
EP2079448A2 (de) | Verbesserte freisetzung von statinen im darm | |
US20010003588A1 (en) | Controlled release dosage form of [R-(Z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2.2.]oct-3-yl)acetonitrile monohydrochloride | |
EP2536402B1 (de) | Zusammensetzungen enthaltend amfetamin und lisdexamfetamin | |
EP3007682B1 (de) | Formulierungen mit modifizierter freisetzung | |
JP2017532363A (ja) | 特に注意欠陥障害の治療のための方法および組成物 | |
KR100591142B1 (ko) | 파록세틴을 활성물질로 함유하는 장용성 서방형 정제 | |
JP5881700B2 (ja) | ブロナンセリン経口放出制御型医薬組成物 | |
WO2007112574A1 (en) | Extended release composition of venlafaxine | |
CN101437494A (zh) | 0级的修饰释放固体剂型 | |
WO2013030726A1 (en) | Programmed drug delivery | |
EP3638211B1 (de) | Pharmazeutische zusammensetzungen mit verzögerter freisetzung | |
EP2331080A1 (de) | Pharmazeutische zusammensetzungen zur verhinderung von darreichungsformaufspaltung | |
US20160175257A1 (en) | Solid oral dosage form of methylphenidate or salts thereof | |
CA3226799A1 (en) | Multiparticulate pharmaceutical composition | |
TWI654977B (zh) | 用於控管噁心及嘔吐之組合物 | |
EP3975719A1 (de) | Formulierung einer pyrimidinylamino-pyrazol-verbindung mit modifizierter freisetzung und behandlungsverfahren | |
AU2017260701A1 (en) | Delayed-release tablets of methylphenidate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AC | Divisional application: reference to earlier application |
Ref document number: 2020995 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR |
|
17P | Request for examination filed |
Effective date: 20121130 |
|
17Q | First examination report despatched |
Effective date: 20130409 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20160922 |
|
GRAJ | Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted |
Free format text: ORIGINAL CODE: EPIDOSDIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAR | Information related to intention to grant a patent recorded |
Free format text: ORIGINAL CODE: EPIDOSNIGR71 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
INTC | Intention to grant announced (deleted) | ||
INTG | Intention to grant announced |
Effective date: 20170223 |
|
AC | Divisional application: reference to earlier application |
Ref document number: 2020995 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 881124 Country of ref document: AT Kind code of ref document: T Effective date: 20170415 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602007050527 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 11 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2626632 Country of ref document: ES Kind code of ref document: T3 Effective date: 20170725 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20170405 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 881124 Country of ref document: AT Kind code of ref document: T Effective date: 20170405 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170706 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170705 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170805 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602007050527 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A Owner name: SPECGX LLC Effective date: 20180119 Ref country code: DE Ref legal event code: R082 Ref document number: 602007050527 Country of ref document: DE Representative=s name: WINTER, BRANDL, FUERNISS, HUEBNER, ROESS, KAIS, DE Ref country code: DE Ref legal event code: R081 Ref document number: 602007050527 Country of ref document: DE Owner name: SPECGX LLC (N.D.GES. D. STAATES DELAWARE), WEB, US Free format text: FORMER OWNER: MALLINCKRODT LLC, HAZELWOOD, MO., US Ref country code: DE Ref legal event code: R082 Ref document number: 602007050527 Country of ref document: DE Representative=s name: BOEHMERT & BOEHMERT ANWALTSPARTNERSCHAFT MBB -, DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R082 Ref document number: 602007050527 Country of ref document: DE Representative=s name: BOEHMERT & BOEHMERT ANWALTSPARTNERSCHAFT MBB -, DE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170531 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170531 |
|
26N | No opposition filed |
Effective date: 20180108 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20180215 AND 20180221 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170509 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20170531 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170509 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 12 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170531 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170509 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20070509 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170405 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20170405 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230601 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20230519 Year of fee payment: 17 Ref country code: FR Payment date: 20230525 Year of fee payment: 17 Ref country code: ES Payment date: 20230601 Year of fee payment: 17 Ref country code: DE Payment date: 20230530 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: TR Payment date: 20230425 Year of fee payment: 17 Ref country code: PL Payment date: 20230419 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20230529 Year of fee payment: 17 |